Breast cancer continues to affect one woman in ten in the western world and despite the phenomenal advances in recent years the mortality rate still remains at around 35%. Current endocrine therapies are based on manipulating the estrogen receptor (ER) by either directly targeting the estrogen receptor with ER modulators such as tamoxifen or faslodex or by reducing levels of circulating estrogen with aromatase inhibitors, such as anastrozole. Regardless of the age of the patient, adjuvant endocrine therapy, of which tamoxifen remains amongst first line, offers substantial potential benefit in terms of reduction in risk of tumour recurrence and death in women with ER positive tumours. However, while most patients initially respond to tamoxifen, in 30-40% of cases these tumours relapse within 5 years of treatment. This precipitates cessation of the regime and the initiation of second line therapy.
The development of resistance to endocrine therapy, and consequent tumour recurrence, is due at least in part to a shift in the phenotype of the tumour cell from steroid dependence to that of steroid independence/growth factor dependence. Much attention has been given in recent years to the targeting of this growth factor pathway, in particular by focusing on the growth factor receptors. Inhibitors of these receptors include herceptin, the monoclonal antibody directed against the growth factor receptor HER2, which has revolutionized the treatment of advanced breast cancer. These therapies however are effective only in a limited (25%) patient population who over-express these receptors and as such their widespread use will ultimately be limited. Despite initial favourable reports from clinical trials regarding inhibitors of both aromatase and growth factor receptors, unanswered questions remain concerning sequencing and duration of adjuvant therapy, particularly with regard to the benefit from ‘priming’ the tumour with tamoxifen. Furthermore due to the overriding efficacy and cost effectiveness of estrogen receptor modulators, such as tamoxifen, it is probable that these will remain important adjuvant treatments for the foreseeable future. There is therefore a pressing need to elucidate the molecular mechanisms underlying resistance to endocrine treatment and to identify patients in whom tumours are likely to recur.